Stimulants (MPH, AMP) for ADHD

Stimulants (psychotonics, psychoanaleptics, stimulants, colloquially: upper; singular: Stimulants) are psychotropic substances that have a stimulating effect by increasing, accelerating or improving nerve activity.
The opposite are tranquilizers (sedatives, colloquially: downers).

ADHD medications are divided into stimulants (methylphenidate, amphetamine medications) and non-stimulants (atomoxetine, guanfacine and others).

• 1. Stimulants from a chemical perspective
• 2. Stimulants as medication versus stimulants as a drug
• 3. Abuse of prescribed stimulants
• 4. Stimulants as ADHD medication reduce the risk of addiction
  • 4.1. ADHD medication reduces the risk of developing addiction
  • 4.2. ADHD medications reduce addictive behavior with existing addiction
• 5. Long-term effects of stimulants
• 6. Side effects of stimulants
  • 6.1. Blood pressure, pulse
  • 6.2. Cardiovascular risks
  • 6.3. Bone problems

1. Stimulants from a chemical perspective¶

• Phenethylamines
  Phenethylamine is the chemical parent substance of all naturally and artificially produced phenethylamines. It is the parent chemical group and is a so-called trace amine, as it is only found in small quantities in the body. Many substances within this large group have a psychotropic effect.
  • Catecholamines
    • Dopamine
    • Noradrenaline
    • Adrenalin
  • Phenylethylamine
    • Methylphenidate
  • Amphetamines
    A group of mostly artificially produced phenethylamines, which are also known as wake-up amines due to their stimulating effect
    • Dexamphetamine
      • Active ingredient in many ADHD amphetamine medications
    • Methamphetamine
      • was developed at the end of the 19th century and used as a war drug (Pervitin, on the market in Germany until 1988; Desoxyn (USA))
      • common in the drug scene as “meth”, “crystal” or “crystal meth”, among others
    • Cathinone.
      These are both natural and artificial amphetamines, which differ only slightly chemically from the main substance amphetamine (amphetamine derivatives).
      • Bupropion

(Thanks to Nephilim)

2. Stimulants as medication versus stimulants as a drug¶

Amphetamines are also traded and consumed illegally as drugs (e.g. as ecstasy, crystal meth).
As with any drug, the amount and method of use determine whether it is helpful or harmful. With amphetamines, the intoxicating effect is caused by

• Massively higher dosage than as a drug
  • Only a high dosage occupies more than 50 % of the dopamine receptors and thus enough to cause a perception of intoxication¹
  • Only the high dosage leads to the release of dopamine via the VMAT2 receptors.
    AMP drugs, which have a purely reuptake-inhibiting effect, do not use this route of action
• Rapid absorption of active ingredients (e.g. through the nose)¹
  • Even a high dosage, which is taken slowly, does not act like a drug
• Short duration of action (a high speed of change in the dopamine level upwards and downwards is crucial)¹

Stimulants are low doses of medication, have a long-term, consistent effect and are also administered orally, which means that the active ingredients are distributed so slowly that no intoxicating effect can occur.
When taken as prescribed by a doctor, there are no known addictive effects, which unfortunately cannot be said of many other medically prescribed drugs.

Immediate release MPH, taken in succession, like sustained release MPH, sets several dopamine maxima (all of which are so low that they do not develop drug effects). Lisdexamfetamine, on the other hand, sets only one maximum and thus causes a more even inhibition of dopamine (and noradrenaline) reuptake.
In order to increase DA and NE levels as evenly as possible with immediate release MPH, it should be administered at shorter intervals (2 to 2.5 hours) than the optimal single dose. So instead of administering 7.5 mg every 3.5 hours (for example), an administration of 5 mg every 2.5 hours would result in a more even DA and NE level and thus better symptom reduction. Stahl illustrates the difference between short-term high/rapidly decreasing stimulant levels (= phasic DA) and low long-term constant stimulant levels (= tonic DA) as the decisive difference between drug effect and curative drug effect.²

3. Abuse of prescribed stimulants¶

A meta-analysis of k = 13 studies showed that half of the studies had a reported prevalence of stimulant abuse in adults of 0%. In other studies, the range was from 2% to 29%. Certain characteristics increased the risk of abuse:³

• older age
• earlier or more frequent use of ADHD medication
• Taking short-acting medication
• a diagnosis of alcohol/substance abuse in the past

Studies show that ADHD medication can only slightly improve cognitive performance, e.g. attention, in people without ADHD. An increase in academic performance was not observed in people without ADHD.⁴
In South Africa, methylphenidate has the highest sales rate in the exam months compared to other months.⁵⁶ The fact that this affects sustained release MPH in particular could also be due to the abnormal price differences (sustained release MPH cost around 8 times more than immediate release MPH in South Africa in 2022)

Due to the inverted-U profile of the effects of dopamine, an increase in dopamine levels in non-affected people (based on an optimal average level) is generally detrimental. At most, severe chronic stress, which lowers dopamine levels, can lead to a dopamine deficiency in non-affected individuals, for which ADHD medication also helps non-affected individuals. We believe it is possible that this could be the case in exam situations. For example, there is ample evidence of abuse of stimulants by non-affected students in exam situations. However, there are no reports of voluntary long-term use after the end of exams by people not affected by ADHD. There is no other explanation for the decline in use after the exam months in South Africa.
In fact, students who abuse stimulants for exam periods have higher than average ADHD symptoms.⁷

in a study of n = 224,469 American students aged 18 to 25, 2.4% reported stimulant abuse in the last 3 months. This rate was 40% higher among people with ADHD who did not receive ADHD medication.⁸

4. Stimulants as ADHD medication reduce the risk of addiction¶

4.1. ADHD medication reduces the risk of developing addiction¶

Stimulants do not increase the risk of developing an addiction, neither to non-medical stimulants⁹ nor to stimulant medication. People with ADHD often enough forget to take their medication, which would not happen with an addictive pressure.
On the contrary, stimulants as ADHD medications significantly and sustainably reduce the risk of addiction. A case report provides an example.¹⁰
One year of MPH treatment resulted in:¹¹

• Internet addiction reduced
• Shopping addiction reduced
• Binge eating reduced
• Sex addiction reduced
• Gambling addiction unchanged

One study reports that factors such as the onset and discontinuation of medication use for ADHD may influence the likelihood of addiction later in life.¹² However, it should be noted that addiction is epidemic in the USA (one in 13 Americans has a diagnosis of addiction), which can be attributed in particular to inappropriate painkiller prescriptions (opioids), which never occurred in Europe. The extent to which the study could be transferred to conditions outside the USA and especially in Europe is unclear.

A meta-analysis of k = 6 studies with n = 1,014 subjects showed a significantly reduced risk of later addiction for participants medicated with stimulants (here: MPH).¹³ The risk of later addiction, whether to alcohol or other substances, was found to be 1.9 times lower (i.e. almost halved).¹⁴
This is consistent with the experiences from the ADHD forum of ADxS.org. Many more people with ADHD report that their craving for alcohol or nicotine has decreased significantly since taking stimulant medication, while reports to the contrary tend to be isolated cases.

Amphetamine drugs are now available as pro-drugs (lisdexamfetamine). This means that they are available in a form in which they are simply ineffective when abused (abusive ingestion in massive overdoses through the nose or intravenously) because they are present in an active substance compound, are only metabolized over many hours in the blood, very slowly, to the active drug substance and therefore cannot trigger a drug high, but can only bring about the healing effect of a flatly rising and falling functional dopamine level.
Daberkow et al¹⁵ show in this Graph under D the slow increase in dopamine (drug) at 1 mg/kg AMP and the rapid increase (drug) at 10 mg/kg AMP. The level development at 1 mg/kg AMP corresponds to the curves known from amphetamine drugs.

4.2. ADHD medications reduce addictive behavior with existing addiction¶

People with ADHD with comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants, corresponding to the reduction in ADHD symptoms¹⁶
Treatment with prolonged-acting mixed amphetamine salts in people with ADHD with comorbid cannabis addiction led to cannabis discontinuation in 15%, compared to 0% cannabis discontinuation with placebo.¹⁷

Nevertheless, for persons with ADHD with a pre-existing acute or previous addiction (dependence) to amphetamines or cocaine, it should be taken into account that the receipt of similarly acting drugs could trigger them to try to abuse them again as a drug.
Other acute or former addictions (alcohol, THC without amphetamine addiction) should barely produce a trigger effect.
Isolated amphetamine abuse (weekend use) in the past is also unlikely to pose a risk and is more likely to be a sign of self-treatment in people with ADHD, even if repeated.
It should also be borne in mind that there are cheaper and easier to obtain substances in every disco and behind every train station that produce considerably more intoxicating effects. In our opinion, the risk of abuse of ADHD medication is rather theoretical. Considering the importance for the treatment of people with ADHD, we doubt that the restrictions make sense from a socio-political point of view.

5. Long-term effects of stimulants¶

One study found a long-term effect when taking stimulants (MPH, lisdexamfetamine) for at least 24 months:¹⁸

• spatial memory
• Sample separation
• Object recognition.

These improvements did not occur immediately after taking the stimulants, but only became significant after 24 months.
The study found no adverse effects on spatial navigation, object recognition memory or pattern separation.

6. Side effects of stimulants¶

6.1. Blood pressure, pulse¶

A meta-analysis with n = 2,665 adults with ADHD found the side effects of stimulants to be:¹⁹

• an increase in the resting heart rate by an average of 5.7 beats per minute
• an increase in systolic blood pressure by an average of 2 mm Hg
• a low rate of clinically significant cardiovascular events (including high blood pressure or tachycardia)

6.2. Cardiovascular risks¶

A meta-analysis reports:²⁰

• 1 out of 7 studies in children found an increased risk of cardiovascular problems
• 2 out of 3 studies on adults found increased risks of cardiovascular problems

An analysis of n = 131,255,418 reports from the WHO international pharmacovigilance database from 1967 to 2023 found 13,344 reports of cardiovascular side effects among the 146,489 reports of ADHD medications. ADHD medications were associated with an overall 60% increased risk of cardiovascular adverse events (ROR 1.60). Women had a higher risk than men. The following occurred:²¹

• Torsade de pointes/QT prolongation
• Cardiomyopathy
• Myocardial infarction

Only amphetamines were associated with

• Heart failure
• Stroke
• Cardiac death/shock

Methylphenidate had the lowest overall association with cardiovascular side effects of all ADHD medications.
Lisdexamfetamine had a weaker association with all cardiovascular side effects than other amphetamine drugs
Atomoxetine showed the second highest association with torsade de pointes/QT prolongation.

A Danish cohort study of n = 8,300 children with ADHD born between 1990 and 1999 found a 2.2-fold risk of cardiovascular problems from stimulants (n = 111 cases):²²

• Hypertension and arrhythmias were the most common.
• MPH increased the risk in a dose-dependent manner. At over 30 mg MPH / day, there was a 2.2-fold risk compared to lower doses.

A Swedish case-controlled registry study of n = 62,060 people aged 6 to 64 years with ADHD found that long-term (up to 14 years) use of ADHD medications compared to no use increased the risk of cardiovascular problems (hypertension and arterial disease, but not arrhythmias, heart failure, ischemic heart disease, thromboembolic disease or cerebrovascular disease)²³

• increased by 8 % in the first 3 years
• increased by 4 % for each additional year

Doses above 45 mg MPH or LDX, above 22.5 mg amphetamine or above 120 mg atomoxetine daily were associated with a higher cardiovascular risk.²³

Heart rate in children and adolescents with ADHD:

• Oros-MPH did not increase the heart rate more than placebo²⁴²⁵
• The non-stimulant atomoxetine increased HR more than placebo²⁴
• Increase under amphetamine or atomoxetine statistically significant, but low on average (≤10 beats per minute)²⁵
• Guanfacine (1-3 mg/day) caused a decrease in heart rate, which returned to normal within one year of use²⁶

Increase in blood pressure:

• under amphetamine or atomoxetine statistically significant, but on average low (≤5 mm Hg) (meta-analysis; k = 18, n = 5,837)²⁵
• Methylphenidate can lead to a small increase in blood pressure (meta-analysis; k = 18, n = 5,837)²⁵
• MPH in adolescents with ADHD taken for at least two years resulted in hypertension in 12.2%, compared to 9.6% with no use²⁷
• Dexmethylphenidate (5-20 mg/day) caused a slight increase in systolic blood pressure, which returned to normal within one year of use²⁶
• Guanfacine (1-3 mg/day) caused a drop in blood pressure, which returned to normal within a year of taking it²⁶

Comorbid eating disorder (binge eating, bulimia nervosa, anorexia nervosa) with ADHD increases cardiovascular risks:²⁸

• Anorexia nervosa shows structural and functional abnormalities that pose the greatest risk of cardiovascular complications
• Bulimia nervosa or purgative anorexia nervosa often show electrolyte disturbances
• Binge rating: Obesity is a known risk factor for cardiovascular risks here
• 60% of adolescents and young adults with an eating disorder develop a substance use disorder in the course of their lives

Comorbid substance abuse (nicotine, alcohol, cannabis) with ADHD increases cardiovascular risks:²⁸

• Cannabis can lead to clinically significant reductions in heart rate variability.
• Cannabis is acutely associated with tachycardia, hypertension, platelet activation and endothelial dysfunction
• Cannabis is chronically associated with cardiovascular disease, cardiomyopathy and arrhythmias
• daily cannabis use increases compared to non-smokers
  • the risk of myocardial infarction by 25
  • the risk of stroke by 42 %

For the overall effect of stimulants on ADHD symptoms, see also the following articles:

• Protective effect of ADHD treatment In the article Consequences of ADHD
• MPH Part 2: Dosage, side effects, contraindications
• Side effects of amphetamine medication

6.3. Bone problems¶

A meta-analysis of k = 44 studies reported that the use of MPH or AMP leads to a deterioration of specific bone properties and biomechanical integrity via downstream effects on osteoblasts and osteoclast-related genes.³⁰

In contrast, it should be borne in mind that stimulants in ADHD massively reduce the risk of (accidental) bone fractures. *More on this in the chapter Consequences of ADHD). *